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A New Focus on Depression

Of all the major illnesses, mental or physical, depression has been one of the toughest to subdue. Despite the ubiquity of antidepressant drugs — there are now 26 to choose from — only a third of patients with major depression will experience a full remission after the first round of treatment, and successive treatments with different drugs will give some relief to just 20 to 25 percent more.

About 30 percent of people with depression have some degree of treatment resistance. And the greater the degree of resistance, the more likely a future relapse, even if the patient continues taking the drug.

Although we have learned much about depression — for example, the recent research showing that the successful treatment of insomnia in depressed patients essentially doubles their response to a drug like Prozac — we still don’t understand its fundamental cause. The old idea that the disease results from a deficiency of a single neurotransmitter like serotonin or dopamine is clearly simplistic and wrong.

Maybe psychiatrists and neuroscientists have something to learn from the successful hunt for the Higgs boson.

Of course a debilitating disease has nothing in common with a subatomic particle, except that both are mysterious and elusive. But it was those very qualities that inspired international teams of physicists to work together for years until they finally identified the boson last year.

Among biomedical scientists, who compete for the same research dollars and want to be first across the finish line with an important finding, such cooperation is hardly the norm. But there are signs that this is changing.

Not long ago, I sat in at a meeting of the Hope for Depression Research Foundation. Audrey Gruss, the knowledgeable and energetic philanthropist who started the foundation, has corralled a group of senior basic and clinical neuroscientists to look for solutions. (It is not the first to try a collaborative approach; others are being sponsored by the MacArthur Foundation and the Pritzker Consortium.)

“A complex problem like depression is much larger than one scientist or lab can handle,” said the leader of the group at the Hope foundation, Huda Akil, a professor of neurosciences and psychiatry at the University of Michigan. “What is great about our collaboration is that we can think about big ideas and take risks without worrying about what grant reviewers” — like the National Institute of Mental Health, the major source of federal funding for psychiatric research — “might think.”

A major goal is to understand which brain circuits and genes are altered by depression, how the environment interacts with these genes, and how to reverse the accumulated biological assaults of this disease. That will require the integration of a wide range of tools, she said: genomics, epigenetics, electrophysiology, animal models, clinical psychiatry.

A major drawback of our current antidepressants is that they rely on animal models that have been used for decades, yielding drugs that all work the same way. Novel drugs require identification of new targets in the brain and better animal models in which to screen them.

So one member of the group, Dr. Joshua Gordon, an associate professor of psychiatry at Columbia, studies new animal models of depression by recording activity in select brain regions in mice that are engaged in depressionlike behavior.

After talking with another group member, Dr. Helen S. Mayberg, a neuroscientist at Emory University, Dr. Gordon modified his approach. Dr. Mayberg has identified a target for deep brain stimulation in patients with treatment-resistant depression: a region called the subgenual cingulate cortex. When it is directly stimulated with electrodes in depressed patients who have failed to respond to nearly all other treatments, many show a brisk positive response.

Dr. Mayberg urged Dr. Gordon to extend the region of his recording to include the mouse analog of this human brain region, so he could more fully capture activity in these different areas of the cortex and understand how they individually contribute to depressionlike behavior in mice.

Another group member, Bruce McEwen, a neuroscientist at Rockefeller University who has done pioneering work on the effects of stress on the brain, is studying rats from Dr. Akil’s lab that have been genetically selected for their propensity to show anxiety and depressionlike behavior.

Among other things, Dr. McEwen is using these rats to study the efficacy of drugs with the potential to act rapidly against depression. Such a drug would be a major boon to psychiatry: We need treatments that can ease the symptoms of depression, and its attendant risk of suicide, in far less time than the two to six weeks that all current antidepressants require to do their work.

Even a high-powered collaboration like this one offers no guarantee of finding effective weapons against intractable depression. After all, it took 50 years to smoke out the Higgs boson, and even at that, there are huge unanswered questions.

But at a time when federal research funds are shrinking and major drug companies have all but shuttered their brain research programs, enlightened philanthropists and entrepreneurs are helping to open a promising new pathway for neuroscience research: collaboration among researchers willing and able to take thoughtful risks and solve big problems.